The present invention relates to the use of compounds known in the art as 5-HT6 receptor antagonists in the treatment of hyperactivity disorders. More particularly the invention relates to the use of such compounds in the treatment of Attention Deficit Hyperactivity Disorder (ADHD).
Attention Deficit Hyperactivity Disorder, which is also referred to in the literature as Attention Deficit Disorder/Hyperactivity Syndrome (ADD/HS), is a condition (or group of conditions) characterised by impulsiveness, distractibility, inappropriate behaviour in social situations and hyperactivity. ADD/HS is reported to have a prevalence of 3-5% (using DSM-IV criteria) in children (Diagnostic and Statistical Manual of Mental Disorders; 4th edition; American Psychiatric Association; 1994). It is believed that some 30-60% of such cases persist into adulthood (Zametkin A. J. and Borcherding B. G., Ann. Rev. Med. 1989, 40:447-51). This disorder can impair social function, learning and/or development and is therefore now recognised as a serious problem. It is further recognised that many children with ADHD go on to develop other comorbid conditions or social problems in adulthood.
In clinical terms ADHD is diagnosed if any one of the three main clinical features viz. inattention, over-activity and impulsiveness, persists in two or more situations, e.g. in both a home and school environment (American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) Washington D.C.; American Psychiatric Association, 1994).
A particularly severe form of ADHD is termed Hyperkinetic Disorder. In Britain, this diagnosis is made only if all three of the main clinical features (inattention, over-activity and impulsiveness) have been present from an early age, persist in more than one situation (e.g. home and school) and impair function (The ICD-10 Classification of Mental and Behavioural Disorders: Diagnostic Criteria for Research. Geneva: World Health Organisation, 1993: 155-7). Reports indicate that 1 in 200 children suffer from hyperkinetic disorder (Taylor E., et al, The Epidemiology of Childhood Hyperactivity, Oxford University Press 1991: 93-113).
There are currently only a few therapeutic agents which are recognised as having efficacy in the treatment of childhood ADHD; at present the drugs of choice are dextroamphetamine, pemoline and in particular methylphenidate (Ritalin,(trademark)). Antidepressants and antipsychotic medications such as risperidone may also be effective in some cases but these are not standard treatments. Although methylphenidate is probably the most widely used drug in the treatment of ADHD it suffers from a number of disadvantages: it is a controlled drug: is extensively metabolised and may cause confusion and hallucinations. Moreover, methylphenidate does not treat one of the three main clinical features of ADHD, namely inattentiveness, and in addition does not normalise ADHD children. There is therefore a need for a new treatment for ADHD and related disorders which demonstrate both an improved pharmacological profile and which do not have the associated disadvantages of currently known therapeutic agents.
The etiology of ADHD is still not well understood. However, there is evidence to suggest that ADHD is associated with abnormalities in the caudate (Ernst et al, Journal of Neuroscience, 1998, 18(15), 5901-5907.). It has now been found that certain compounds, known in the art as 5-HT6 receptor antagonists, selectively increases activity of the nigro-striatal dopamine pathway and could therefore, specifically alleviate these abnormalities. The compounds of the present invention have additional effects on the central nervous system, namely, an increase in cognitive function. Consequently, such compounds have utility in the treatment of ADHD and related disorders.
The present invention therefore provides, in a first aspect, the use of a compound having 5-HT6 receptor antagonist activity in the manufacture of a medicament for use in the treatment of ADHD.
A 5-HT6 antagonist for use in this invention must be selective for 5-HT6 receptors. Where used herein, this is intended to mean that the 5-HT6 antagonist must have a greater than 10-fold selectivity for this receptor over other binding sites within the CNS, in particular, other 5-HT receptor sub-types and dopaminergic receptors. The most preferred compounds of this invention demonstrate greater than 100-fold selectivity for 5-HT6 receptors. The selectivity of the compounds of this invention for 5-HT6 receptors can be determined using binding assays methods which are well known to those skilled in the art.